PI3 Kinases are a family of lipid kinases that have been found to play a key role in the regulation of many cellular processes including proliferation, survival, carbohydrate metabolism, and motility. Recent evidence suggests that some members of the PI3K family have an important role in cancer. For example, emerging evidence for functional specialization of PI3K isoforms has suggested that isoform selective inhibitors may prove to be useful anticancer drugs. (Endocrine-Related Cancer, Stein, R. C., Soc. For Endocrinology, (2001) 8, 237-248.)
PI3Ks are considered to have an important role in intracellular signal transduction in health and disease. In particular, the PI3Ks generate and convey signals that have an important role in cancer. PI3Ks are ubiquitously expressed, are activated by a high proportion of cell surface receptors, especially those linked to tyrosine kinases, and influence a variety of cellular functions and events. Although some PI3K activity is likely to be essential for cellular health, the PI3Ks are a rather diverse group of enzymes for which there is increasing evidence of functional specialization. This opens up the possibility of developing isoform-selective inhibitors that could be used to treat cancer with limited toxicity.
The primary enzymatic activity of the PI3K is the phosphorylation of inositol lipids (phosphoinositides) on the 3-position of the inositol headgroup. PI3 kinases catalyse the addition of phosphate to the 3′-OH position of the inositol ring of inositol lipids generating phosphatidyl inositol monophosphate, phosphatidyl inositol diphosphate and phosphatidyl inositol triphosphate (Whitman et al, 1988, Stephens et al 1989 and 1991).
There are a total of eight mammalian PI3Ks, which have been divided into three main classes on the basis of sequence homology, in vitro substrate preference and method of activation and regulation. Enzymes of a first class have a broad substrate specificity and phosphorylate PtdIns, PtdIns(4)P and PtdIns(4,5)P2. Class I PI3Ks include mammalian p110α, p110β, p110δ and p110γ. (Hiles et al, 1192; Hu et al, 1993; Stephens et al, 1994; Stoyanov et al, 1995). Different members of the PI3K family generate different lipid products. To date, four 3-phosphorylated inositol lipids have been identified in vivo. These lipids are bound by proteins that contain the appropriate lipid recognition module and that act to transmit the PI3K signal onwards.
The most familiar form of PI3K is the PI3Kα heterodimer, which consists of a 110 kDa catalytic subunit and an 85 kDa regulatory/adapter subunit, p85α. (Endocrine-Related Cancer (2001) 8, 237-248.)
The catalytic subunit contains a kinase domain that uses ATP to phosphorylate PtdIns, PtdIns4P and PtdIns (4,5)P2. The major product of class I PI3Ks is PtIns(3,4,5)P3, or PIP3, which is required for translocation of protein kinase B (PKB, AKT1) to the cell membrane where it is phosphorylated and activated by upstream kinases. PTEN, a tumor suppressor, dephosphorylates PIP3. The effect of PTEN on cell death is mediated through the PI3K/AKT1 pathway.
PI3Kα has been implicated in the control of cytoskeletal reorganization, apoptosis, vesicular trafficking and proliferation and differentiation processes. Increased copy number and expression of the p110alpha gene (PIK3CA) is associated with a number of malignancies such as ovarian cancer (Campbell et al., Cancer Res 2004, 64, 7678-7681; Levine et al., Clin Cancer Res 2005, 11, 2875-2878; Wang et al., Hum Mutat 2005, 25, 322; Lee et al., Gynecol Oncol 2005, 97, 26-34), cervical cancer, breast cancer (Bachman, et al. Cancer Biol Ther 2004, 3, 112-115; Levine, et al., supra; Li et al., Breast Cancer Res Treat 2006, 96, 91-95; Saal et al., Cancer Res 2005, 65, 2554-2559; Samuels and Velculescu, Cell Cycle 2004, 3, 1221-1224), colorectal cancer (Samuels, et al. Science 2004, 304, 554; Velho et al. Eur J Cancer 2005, 41, 1649-1654), endometrial cancer (Oda et al. Cancer Res. 2005, 65, 10669-10673), gastric carcinomas (Byun et al., Int J Cancer 2003, 104, 318-327; Li et al., supra; Velho et al., supra; Lee et al., Oncogene 2005, 24, 1477-1480), hepatocellular carcinoma (Lee et al., id.), small and non-small cell lung cancer (Tang et al., Lung Cancer 2006, 51, 181-191; Massion et al., Am J Respir Crit. Care Med 2004, 17 ft 1088-1094), thyroid carcinoma (Wu et al., J Clin Endocrinol Metab 2005, 90, 46884693), acute myelogenous leukemia (AML) (Sujobert et al., Blood 1997, 106, 1063-1066), chronic myelogenous leukemia (CML) (Hickey and Cotter J Biol Chem 2006, 281, 2441-2450), and glioblastomas (Hartmann et al. Acta Neuropathol (Berl) 2005, 109, 639-642; Samuels et al., supra). In view of the important role of PI3Kα in biological processes and disease states, inhibitors of this protein kinase are desirable.